Optically enhanced chiral ionic liquids

ABSTRACT

The invention relates to the use of optically enhanced chiral ionic liquids, particularly for gas chromatography and as a reaction solvent. Specific optically enhanced chiral cationic liquids are described as is a class of optically enhanced chiral anionic liquids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S.Provisional Patent Application No. 60/586,782 filed Jul. 9, 2004, thedisclosure of which is hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

Nonchiral ionic liquids have been used as solvents in the past. Chiralliquids that are racemic have been used as solvents as well. SeeYasuhiro Ishida et al., “Design and synthesis of a novelimidazolium-based ionic liquid with planar chirality,” Chem. Commun.2240-41 (2002) (a copyright of the Royal Society of Chemistry). Solventsof enantiomerically enhanced chiral cations have also been described.See Wasserscheid et al., “Synthesis and properties of ionic liquidsderived from the ‘chiral pool’,” Chem. Commun. 200-01 (2002) andWeiliang Bao et al., “Synthesis of Chiral Ionic Liquids from NaturalAmino Acids,” 68 J. Org. Chem. 591 (2003). These were not described asvehicles for conducting subsequent reactions.

Earle et al. disclosed reactions of dienes and dienophiles in varioussolvents including [bmim] [lactate], an ionic liquid with a chiral anionof unreported configuration or purity. The result was not asymmetric.See Martyn J. Earle et al., “Diels-Alder reactions in ionic liquids,”Green Chem. 23-25 (1999). Chiral nonionic materials have also been usedas the stationary phases in gas chromatography. (See U.S. Pat. Nos.4,948,395 and 5,064,944.)

SUMMARY OF THE INVENTION

The present invention relates to optically enhanced chiral ionic liquids(“OCIL”). These are salts which are liquids having a melting point of100° C. or less. Preferably, they are liquid at room temperature (18° C.to about 25° C.) or less.

OCILs in accordance with the present invention are liquid materials madefrom chiral compounds and/or their salt mixtures and associationsthereof. “Chiral” as used herein means that the compound has at leastone stereogenic center or axis (also referred to as a “chiral center” or“asymmetric center”). “Ionic” as used in connection with OCILs inaccordance with the present invention includes cations, anions or saltsthereof. A chiral anion is an anion which contains a stereogenic centeror axis. A chiral cation is a cation which contains a stereogenic centeror axis. OCILs may also be salts, mixtures or associations of bothchiral cations and chiral anions. Thus a chiral anion may be associatedwith a nonchiral cation, thus forming a “chiral anion containing OCIL,”also referred to herein as a “chiral anion” or an “anionic OCIL,” or maybe associated with a chiral cation. Similarly, a chiral cation may beassociated with a nonchiral anion thus forming a “chiral cationcontaining OCIL,” also referred to herein as a “chiral cation” or a“cationic OCIL” or it may be associated with a chiral anion.

Many of the compounds discussed herein are enantiomers, pairs of mirrorimage compounds with opposite optical configurations, (each referred toas an enantiomer or an optical isomer as appropriate). These can bepresent in the form of either a racemic (50:50) mixture or an opticallyenhanced mixtures in which one of the enantiomers is present in anamount which is greater than the other. “Optically enhanced,” even whendescribed in the context of an optically enhanced mixture, also is meantto include an optically pure material which is substantially orcompletely only one of the two enantiomers. The OCILs of the inventionare not limited to enantiomers, but may include diastereoisomers,compounds that have more than one stereogenic center. A compound of thistype with, for example, 2 stereogenic centers can be thought of for theinvention as producing two distinct sets of enantiomers. Of course,while each enantiomer will be present as an equal mixture, one pair ofenantiomers may be present in a greater percentage than the other. AnOCIL in the case of diastereoisomers is a compound which meets the othercriteria set forth herein wherein at least one of the enantiomers ispresent in an enhanced amount relative to its corresponding enantiomer.The other enantiomeric pair may still be racemic relative to each other,or one of optical isomers of that pair of enantiomers may also beoptically enhanced. Thus it is still proper, in the context of theinvention to refer to racemic mixtures and enantiomers, even though theymay be diastereoisomers relative to other possible optical isomers.

One aspect of the present invention is the discovery of a novel class ofchiral cationic containing OCIL molecules (often used synonymously withthe term “compound” herein or as the context indicates) and inparticular, those individually identified herein. Another aspect of theinvention are chiral cationic containing OCILs in which at least oneenantiomer is enhanced by at least about 2% relative to the other.Another aspect of the invention are chiral cationic containing OCILs inwhich at least one enantiomer is enhanced by at least about 10% relativeto the other. Another aspect of the invention are chiral cationiccontaining OCILs in which at least one enantiomer is enhanced by atleast about 20% relative to the other. In another aspect, the inventionrelates to chiral cationic containing OCIL molecules which are otherthan N-alkyl-N-methylephedrinium salts, and/or those shown in Table A.

Another aspect of the present invention is the discovery of a class ofanionic containing OCILs. One aspect of the invention are chiral anionicOCILs in which at least one enantiomer is enhanced by at least about 2%relative to the other. Another aspect of the invention are chiralanionic containing OCILs in which at least one enantiomer is enhanced byat least about 10% relative to the other. Another aspect of theinvention are chiral anionic containing OCILs in which at least oneenantiomer is enhanced by at least about 20% relative to the other. Inanother aspect of the invention, there are provided anionic containingOCILs that are not lactates.

In yet another aspect of the present invention there is provided a classof OCILs which are salts where both anions and cations are chiral, andat least one, and preferably both, are optically enhanced. In anotherembodiment of this aspect of the present invention, both the cationicand anionic portions of the OCIL are chiral, but have an oppositeoptical rotation. Thus, for example, the cation may be (R) and the anion(S). Indeed, in this situation, there could be each of a cation with an(R) configuration, a cation with an (S) configuration, an anion with an(R) configuration and an anion with an (S) configuration, in variousproportions. Thus the combinations of chiral cation and chiral anioninclude (R)(S), (S)(R), (R)(R), (S)(S), and preferably these aresubstantially pure.

In yet another aspect of the present invention there is provided asolvent that may be used for dissolving, suspending, gelling,emulsifying, dispersing and forming colloids, comprising chiral anionic,chiral cationic or mixed anionic and cationic containing OCILs. Thesemay include those of Table A.

Another aspect of the present invention is a method of conducting achemical reaction in the presence of at least one chiral cationic and/orchiral anionic containing OCIL. These may include those of Table A. TheOCIL can be present as a part of a solvent system or as the reactionmedium or carrier for one or more of the reactants or even as areactant. Also considered part of the invention are molecules, whetherchiral or achiral, racemic or not, pharmaceutically or chemicallyactive/reactive or inert, finished product or intermediate resultingfrom a chemical reaction conducted in the presence of any OCIL.Preferred are non-racemic compounds synthesized asymmetrically using anOCIL in accordance with the invention. Also preferred are any reactionsthat are enantiomerically (or optical isomerically) selective. Alsopreferred are reactions using or in the presence of OCILs which involvethe use of a charged species (other than the OCIL) as a reactant,reagent, intermediate or final product.

Reactions include, without limitation, condensation, hydrogenation,nucleophilic and electrophilic substitutions, deracemization, asymmetricsynthesis, esterification, ether formation, halogenation, polymerizationreactions, chain propagation, cross-linking, salt formation,precipitation or crystallization and the like. Deracemization andasymmetric synthesis reactions are particularly preferred. Alsopreferred are any reaction of the type noted immediately above that isenantiomerically (or optical isomerically) selective. Also preferred arethose reactions noted immediately above using OCILs which involve theuse of a charged species (other than the OCIL) as a reactant, reagent,intermediate or final product. In accordance with another aspect of theinvention, any of the foregoing reactions are conducted in the presenceof an OCIL which is enhanced such that it is substantially opticallypure (at least 90% of one enantiomer relative to the other enantiomer).Preferably these reactions using substantially pure OCILs includeasymmetric synthesis, deracimization, reactions using charged speciesand enantioselective processes.

A particularly preferred aspect of the present invention is anasymmetric synthesis of a compound comprising the steps of conducting achemical reaction on at least one reactant which is in the presence ofan OCIL to produce a reaction product. The reaction product is recoveredand it is optically active, i.e., it has a stereogenic center or axis.One enantiomer of the reaction product will be present in an amount thatis greater than the other enantiomer, usually at least about 2%difference or more (52:48%). Preferably the OCIL is the solvent. Morepreferably, at least a 10% difference, even more preferably at least a20% difference, even more preferably a substantially pure OCIL is foundbetween the content of enantiomers.

Another particularly preferred aspect of the present invention is aderacemizing reaction wherein a reactant which is in the presence of anOCIL is reacted to form a reaction product. The reactant is racemic andthe reaction product, while optically active, is not racemic. Again,preferably the amount of one enantiomer is at least 2% greater than thatof the other (52:48%), more preferably one reaction product is enhancedso at least about 10% more of one enantiomer is present compared to theother, even more preferably the difference is at least about 20%, andmost preferred is substantially pure. Preferably the OCIL is a solvent.The asymmetric products of these reactions run in the presence of anOCIL are also claimed. These reaction products may also be separated toproduce a substantially optically pure reaction product.

Another aspect of the present invention relates to the use of cationicand/or anionic OCILs as the stationary phase or support in columnsprepared for chromatography including liquid chromatography, gaschromatography (“GC”) and in particular capillary GC. In particularthere is provided a column for use in chromatography comprising: acolumn and a stationary phase which is an OCIL associated therewith. AnyOCIL may be used as a stationary phase. In one embodiment, the column isa capillary and the OCIL stationary phase is coated on an inner surfaceof said capillary. The column in accordance with the invention may alsobe a packed column wherein the stationary phase is absorbed, adsorbed orcoated on a solid support which is packed into the column.

The invention also includes methods of separating compounds comprisingthe steps of: mixing, dissolving, dispersing or suspending opticalisomers in a mobile phase which can be a gas or a liquid depending uponthe type of chromatography, introducing the compounds to be separatedinto a column that includes at least one OCIL, either coated on theinside thereof or as part of a packing as a stationary phase, andadvancing the mobile phase and at least one of the compounds to beseparated through the column so as to resolve at least one of compoundsto be separated. In a particularly preferred aspect of the invention,the compounds to be separated are optical isomers.

DETAILED DESCRIPTION

By “optically enhanced” it is understood that the chiral compounds ofthe invention are not present in a racemic mixture (both enantiomerspresent in approximately the same percentage). Instead, in accordancewith the present invention, at least one of the enantiomers is presentin a greater percentage. As noted previously, this applies todiastereomers as well wherein at least one of the enantiomers of one ofthe pairs of optical isomers which are identical but for theirconfiguration is present in an amount that is greater than the other.More preferably, the one enantiomer is present in an amount of at leastabout 2.0% greater than the other enantiomer by mole percent or weightpercent, as is appropriate. More preferably, one of the optical isomerswill be present in an amount of at least about 10% greater than theother and even more preferably an amount of at least about 20% than theother optical isomer of a pair of enantiomers. Even more preferably,such compounds are “substantially optically pure,” wherein about 90% ormore of the compound in question will be a single enantiomer. This is ofcourse relative to the other enantiomer. Diastereomers with twostereogenic centers, for example, could be substantially optically purein the context of the invention if it had 90% of one optical isomer, 10%of its enantiomer, yet 53 percent of the total composition was a racemicmixture of the other set of enantiomers. Most preferably, an OCIL willhave at least one enantiomer be present in 95% or greater relative tothe other.

In the case of a mixed solvent or stationary phase of two or more chiralionic liquids, it is not necessary that all of the liquids be opticallyenhanced OCILs. One or more may be racemic as long as at least one isoptically enhanced.

OCILs have been found to have many uses. It has been found that they areuseful as solvents, dispersants, gelling agents, emulsifying agents,colloid forming agents, and suspending agents. Indeed, because of theirability to interact on almost any level with almost any other molecule,OCILs may often be substituted, in whole or in part, for traditionalorganic solvents and water. OCILs can interact not only ionically, butalso through, for example, dipole interaction, hydrogen bonding, pi-pi(n-n) interaction, dispersion interactions and even steric forces. Thismakes them useful in chemical reactions, whether used as a reactant, asolvent, or merely present during a reaction. In addition, the abilityto use a material that is at least predominantly one optical isomer oranother provides another dimension to research and manufacturing. Itallows for potentially different interactions, using a solvent of thesame chemical. The enhanced level of one optical isomer, or preferably,their substantially optically pure nature, will allow them to interactin previously unimagined ways. This is particularly true for mixtures ofchiral cations and chiral anions which my have the same optical rotationof may have opposite rotations.

These OCILs are considered “green” in that they are recyclablealternatives to volatile organic solvents. They are air and moisturestable, have excellent solubilizing properties and virtually no vaporpressure. They are nonaqueous, although they can be mixed with water,and therefore can be used in a variety of situations where water isinappropriate.

OCILs in accordance with one aspect of the present invention includeoptically enhanced chiral cations such as, without limitation,(−)-N-Benzyl-N-methylephedrinium.NTf₂ Isoleucine-based ILs, as either anester or an alcohol, (−)Cotinine.TfO, D(+)-Carnitinenitrile.NTf₂,1-((R)-1,2-propanediol)-3-methylimidazolium chloride, (−)-ScopolamineN-butyl.NTf₂ and (+)-chloromethyl methyl ether imidazolium IL. Theirstructures are as follows:

Some of these chiral cationic containing OCILs can be produced by thefollowing general reactions:

The above are merely examples of chiral cationic containing OCILs inaccordance with one aspect of the present invention. Each areindividually considered to be part of the invention. Other cationicOCILs can be produced by methods described in the art. See Wassefscheidand Bao, supra. To qualify as a chiral cationic containing OCIL, amolecule should meet at least some of the following criteria. It shouldhave at least one stereogenic center or axis and be capable of beingsynthesized as an ionic material which has a melting point of 100° C. orless, and most preferably be a liquid at room temperature (18° C.-25°C.) or below. It should contain a greater amount of one optical isomerrelative to its enantiomer optical isomers of the same molecule in thesystem or mixture. Preferably, it is substantially optically pure.Preferably, at least 95% w/w of at least one enantiomer of the moleculeis in the form of one optical isomer. To be a chiral cationic containingOCIL, it must also have a positive charge overall.

The class of novel chiral cation containing OCILs excludes thesemolecules as shown in Table A. TABLE A 1

2

3

4

5

6

7

8

9

10

11

12

The molecules shown in Table A having an enhanced optical purity and inparticular a purity whereby one enantiomer is present in an amount of atleast about 10% greater than the other, more preferably 20% greater thanthe other, and even more preferably substantially optically pure arecontemplated as part of the invention. Moreover, the use of themolecules shown in Table A as a stationary phase in chromatography, as asolvent or other use in chemical reactions described herein are alsoconsidered part of the invention.

OCILs in accordance with the present invention also include those thatare anionic. These have the same overall properties as the chiralcationic containing OCILs except that they have the opposite charge.These chiral anionic containing OCILs include, but are not limited to,those with the following structures:

This material can be made by the following general reaction:

Other non-limiting examples of chiral anions for OCILs (illustrated witha sodium cation and thus more correctly are —O⁻ Na⁺):

A general reaction which can be used to produce anionic OCILs is asfollows:

An anion exchange reaction can take place on the OH⁻ form strong anionexchange resin between an achiral or chiral IL containing anexchangeable anion (such as Br⁻, I⁻) and the resin. And then thehydroxide IL can further react with chiral compounds by means ofcarboxylic acid group. This finally results in anionic OCILs.

Salts created from either chiral cation containing OCILs and/or chiralanion containing OCILs are also included. These include an OCIL and acounter ion. Counter ions include, without limitation, PF₆—,[(CF₃SO₂)₂N—], (CF₃)SO₂ ⁻, Cl—, BMIM (butyl methyl imidazolium).Mixtures of these can also be created where the chiral anion containingOCIL and chiral cation containing OCIL are associated, as salts actingas counter ions for each other or disassociated. Such salts can becreated from, for example, any of the anionic OCILs and cationic OCILsidentified herein.

Another preferred aspect of the present invention involves conducting achemical reaction in the presence of an OCIL, more preferably using anOCIL as a reaction medium, reaction solvent or cosolvent to form areaction product. It is preferred that such OCILs be substantiallyoptically pure. These reactions involve contacting or mixing one or moreOCILs in accordance with the present invention with at least onereactant and causing a reaction to take place wherein some change occursto the reactant (the “reaction product”). This change may be a change inphysical state such as precipitating or melting, or maybe a change in areactant's structure such as ionization, creation of a free radical andthe like. The reaction may also include chemical reorganizations and/oroxidation/reduction reactions such as transfer of an aldehyde to ketoneor alcohol to acid. Movement of an unsaturated bond, a change is aresonance, etc are also contemplated. Chemical reaction can alsoinclude: hydration, condensation, hydrogenation, nucleophilic andelectrophilic substitutions, cyclization, esterification, etherformation, halogenation, polymerization reactions, chain propagation,cross-linking, salt formation, crystallization, nucleophilic orelectrophilic addition or substitution, saturation or unsaturation.These are just some of the reactions which are possible. While the OCILsmay participate in or facilitate these reactions, they generally willnot actually be a participant in that they will generally not be part ofthe resulting chemical. Of course, it is not unusual for solvents to becontained within various materials such as crystalline materials in theform of solvates and that is not excluded.

Reactions that can be run using OCILs in accordance with the presentinvention include, without limitation, the following:

Oxidation

-   -   1. Oxidation of sulfides, selenides and amines to the        corresponding oxides by NaIO₄. plus rearrangement of the        corresponding allylic oxides to allylic alcohols.    -   2. Oxidation of alkenes to cis-1,2-diols by KMnO₄, OSO₄, and        cat. OSO₄ plus reoxidant.    -   3. Oxidation of alkenes to trans-1,2-diols by KHSO₅.KHSO₄.K₂SO₄        plus water.    -   4. Oxidation of 2-naphthols to binaphthols by CuCl₂.4H₂O and        FeCl₃.6H₂O and oxidation of 2-naphthylamines to binaphthyl        diamines by CuCl₂.4H₂O.    -   5. Olefin epoxidation by peracids; H₂O₂ plus urea, nitriles,        tungstate, molybdate and vanadyl reagents; NaOCl plus Cr— or        Mn(salen) complexes; NaIO₄ plus Mn(III) or cat. RuCl₃; KMnO₄        plus CuSO₄; methyltrioxorhenium and KHSO₅.KHSO₄.K₂SO₄.    -   6. Kinetic resolution of 2° alcohols [1-phenylethyl alcohol and        2-butanol] by oxidation with KMnO₄, tetra-N-propylammonium        perruthenate and other oxidants.

Reductions

-   -   1. Reduction of ketones [PhCOMe and ethyl acetoacetate as model        systems] to alcohols by NaBH₄, NaHB(OMe)₃, NaHB(OAc)₃ and        NaH₃BCN.    -   2. Reductive amination of ketones [PhCOMe and cyclohexyl methyl        ketone as model systems] by various 10 and 20 amines using        NaH₃BCN.

Pericyclic Reactions

-   -   1. Diels-Alder, hetero Diels-Alder and inverse electron-demand        Diels-Alder reactions, particularly reactions that are        reversible like those of furan. not run in lactate.    -   2. Cope and oxy-Cope rearrangements.    -   3. Claisen rearrangement.

Pd-Catalyzed Processes

-   -   1. Alkylation of allylic acetates by amines, stabilized        carbanions and other nucleophiles.    -   2. Inter- and intramolecular Heck reactions using aryl        halides/triflates, cycloalkenes and Pd(0).    -   3. Reaction of ArI(OTf) with R¹CH═CR²CHR³OH to give        ArCHR¹CHR²COR³.    -   3. Suzuki reaction of hindered aryl halides/triflates and        arylboronic acids to form atropisomers.    -   4. Pd(II)-catalyzed cyclization of 2-allylic phenols to        2,3-dihydrobenzofurans.    -   5. Pd(0)-catalyzed annulation of 1,2-, 1,3-, and 1,4-dienes by        2-haloanilines and -phenols.    -   6. Hydroesterification of styrenes to 2-arylpropionic acids and        esters.

Other Transition Metal-Catalyzed Processes

-   -   1. Hydroformulation of internal olefins [cis-3-hexene,        cyclopentene and cyclohexene].    -   2. Hydrogenation of RR′C═CH₂, H₂C═C(NHAc) CO₂H(R),        H₂C═CArCO₂H(R) and Baylis-Hillman adducts.    -   3. Pauson-Khand reaction.    -   4. Conversion of RCH═CH₂ and N₂CHCO₂R′ to cyclopropane esters.    -   5. Inter- and intramolecular hydroamination and        hydroalkoxylation of alkenes by PtCl₂ or Zn(OTF)₂.

Condensation Reactions

-   -   1. Michael reactions [cyclohexenone and MeCOCH₂COMe or        EtO₂CCH₂CO₂Et].    -   2. Aldol [MeCHO] reaction.    -   3. Claisen condensation [ethyl propionate and ethyl        phenylacetate].    -   4. Henry reaction of aldehydes [MeCHO and PhCHO] with        nitroalkanes [MeNO₂].    -   5. Baylis-Hillman reaction [PhCHO and acrylates, acrylonitrile        and methyl vinyl ketone using DABCO and BU₃P].    -   6. Cyanohydrin and silyl cyanohydrin formation from aldehydes        [PhCHO].    -   7. Strecker synthesis of RCH(NH₂)CN from RCHO, NH₃ and HCN.    -   8. Passerini synthesis of R¹CH(O₂CR²)CONHR³ from R¹CHO, R²CO₂H        and R³NC.    -   9. Ugi synthesis of R¹CH(NHR⁴COR²)CONHR³ from R¹CHO, R²CO₂H and        R³NC and R⁴NH₂.    -   10. Sc(OTf)₃-catalyzed condensation of ArCHO, PhNH₂ and P(OEt)₃        to industrially important ArCH(NHPh) PO(OEt) 2.

Alkylation Reactions

-   -   1. Alkylation of enamines [cyclohexanone pyrrolidine enamine and        MeI].    -   2. Alkylation of unsymmetrical dicarbonyl compounds [ethyl        acetoacetate, PhCOCH₂CO₂Et, PhCOCH₂COCH₃].    -   3. Friedel-Crafts arylation by 20 alkyl halides and triflates in        non-alcohol containing CILs.

Other Organic Reactions

-   -   1. SN² reactions of 20 alkyl halides [PhCHBrMe model system]        with various nucleophiles [NaOAc, NaN₃, NaOMe, NaSPh, NaOPh and        Na(acac)] for the kinetic resolution of organic halides and        synthesis of chiral products.    -   2. SN² ring opening of symmetrical epoxides [cis-2-butene oxide,        cyclopentene oxide] by various nucleophiles.    -   3. Kinetic resolution of 20 alkyl esters [20 butyl and phenethyl        acetates and benzoates] by hydrolysis and transesterification        [MeOH and EtOH].

Particularly preferred are those reactions discussed above that areenantiomerically selective (applicable to diastereomers as notedpreviously) those that involve a changed reactant, reagent, intermediateor product, other than the OCIL. Also preferred are those reactions runin an OCIL that is substantially optically pure (at least 90 of oneenantiomer relative to the other) as well as those run using chiralcationic containing OCILs and chiral anionic containing OCILs that arenot lactates. Combinations of these are also preferred, such as, by wayof a non-limiting example, those enantiomerically selective reactionsrun in a chiral anionic containing OCIL that is substantially opticallypure. Many of these reactions, run in an OCIL, are particularlypreferred as they permit the asymmetric synthesis of one enantiomer overanother. This is a particularly preferred aspect of the invention.

A particularly preferred type of reaction in accordance with the presentinvention is deracemization. A deracemization reaction allows for thetransformation of a racemic mixture of a chiral carbon-containingcompound to a mixture in which one optical isomer predominates.Preferably, the one resulting optical isomer will be present in anamount greater than any other optical isomer of the same compoundpresent. In a racemic mixture of enantiomers from a single chiralcenter, following a reaction in the presence of an OCIL, preferably oneenantiomer will be provided in an amount greater than 50% with thebalance being the other. In a particularly preferred aspect of thepresent invention, the deracemization reaction provides at least a 10%increase in the relative percentage of one enantiomer versus the other.More preferably, the deracemization reaction provides for a significantincrease in one optical isomer over another. Even more preferred, theresulting mixture is substantially enantiomerically pure (90% orgreater). Most preferably, the reaction in the presence of an OCIL willproduce an enantiomerically pure material (99% of one optional isomer ormore).

An example of a deracemization reaction run using an OCIL is:

This is a thermal racimization/deracimization reaction of a chiral vinylsulfoxide. The reactant exists as a racemate, a 50:50 mixture ofenantiomers, at equilibrium. By dissolving this reactant into an OCIL inaccordance with the present invention (both N,N-dimethylephedrinium and(−)-N-benzyl-N-methylephedrinium were used successfully) and heating to50° C.-75° C., followed by cooling to room temperature, deracemizationoccurred.

Without wishing to be bound by any theory of appreciation, it isbelieved that the reason the deracemization works so well, is the factthat the sulfoxide to sulfonate rearrangement is reversible and the OCILmore strongly binds to one of the sulfoxide enantiomers than the other,which eventually allows one to convert more of the racemate into oneenantiomer. Other factors which are believed to favor one enantiomerover the other include unique ability of OCILs to hydrogen bond througha neighboring alcohol group to functionality in the substrate, furtherstabilizing one OCIL complex over another. This may be the driving forcebehind the relatively high enantioselectivity of the photochemicalrearrangement discussed earlier.

Another preferred reaction in accordance with the present invention is areaction wherein a nonchiral or achiral starting material is reacted andconverted into a chiral product. Even more preferably, the resultingchiral product is not a racemate. One of the optical isomers willpredominate. An example of such a reaction run using an OCIL is:

The starting material was achiral. After a reaction in conventionalsolvents, a racemic mixture would result. However, when run in an OCILin accordance with the present invention, ((+)-chloromethyl methyl etherimidazolium IL), with UV applied at about 254 nm at room temperature,one of the optical isomers predominated (60:40). This reaction has alsobeen run in N,N-dimethylephedrinium and resulted in an increase in thepercentage of one enantiomer.

Other forms of asymmetric synthesis (producing one optical isomer ingreater quantities relative to others) in the presence of an OCIL are apreferred embodiment of this aspect of the invention. A non-limitinglist of such reactions was provided above.

Another preferred embodiment in accordance with the present inventioninvolves the use of OCILs as the stationary phase in columns used inliquid chromatography (LC, HPLC) and gas chromatography (“GC”),preferably capillary columns used in gas chromatography. These can beused for separation of optical isomers of chiral materials. Because oftheir ionic character, OCILs may be used to separate materials whicheven chiral, but nonionic materials, cannot separate. Any OCIL may beused in accordance with the present invention including PCOCILs andanionic OCILs.

OCILs may be coated onto capillary columns as follows. The entire columnis filled with a solution, typically of a cosolvent such as methylenechloride, diethyl ether or pentane) mixed with an OCIL having aconcentration appropriate for the deposition of a film of the desiredthickness. Typical concentrations of the OCIL is between 0.2-0.3%. This,however, may vary as needed. After filling, one end of the column issealed, and the other end is connected to a high vacuum pump with anadjustment valve and placed in a water bath. As the volatile non-OCILsslowly evaporate, the solvent front in the capillary retreats back downthe fused silica tube leaving a coating of OCILs on the wall. Theprocedure is continued (with periodic increases in the vacuum to keepthe vaporization rate constant) until all the cosolvent has evaporatedand, except for an even coating of the OCILs, now called a stationaryphase, the column is empty. These columns are then placed into and usedin various gas chromatographs in accordance with particular procedureswhich may be unique to the separation techniques employed and/or to theequipment used.

The synthesis of (1S,2R)-(+)-N,N-dimethylephedriniumtrifluoromethanesulfonimide, (1R,2S)-(−)-N,N-dimethylephedriniumtrifluoromethanesulfonimide, (1S,2S)-(+)-N,N-dimethylpseudoephedriniumtrifluoromethanesulfonimide are described elsewhere.²² Briefly,N-Methylephedrine is dissolved in dichloromethane and equimolar dimethylsulfate is slowly added. The solvent is removed under reduced pressureand the residue dissolved in water. Addition of an aqueous solution ofequimolar of lithium trifluoromethanesulfonimide will lead to theseparation of an ionic liquid phase which then is washed three timeswith water. The final product is heated under reduced pressure at 100°C. to eliminate remaining water.

All capillary columns are coated by static coating method at 40° C.using a 0.25% (w/v) of the IL stationary phase dissolved indichloromethane. Following the coating process, the coated columns areflushed with dry helium gas overnight and conditioned from 40 to 120° C.at 1° C./min. Column efficiency is tested by naphthalene at 100° C. Allcolumns used will have an efficiency of over 2100 plates/meter.

The racemic test compounds are dissolved in dichloromethane. AHewlett-Packed model 6890 gas chromatograph and a Hewlett-Packard 6890series integrator is used for all separations. Split injection and flameionization detection are utilized with injection and detectiontemperatures of 250° C. Helium is used as the carrier gas with a flowrate of 1.0 mL/min.

A large number of compounds have been injected into the OCIL columnslike those discussed above, which included alcohols, amines, organicacids and oxides. The racemic mixtures listed in Table 1 can beenantiomerically resolved on the OCIL stationary phases. Thechromatograms were obtained on an 8 meters(1S,2R)-(+)-N,N-dimethylephedrinium trifluoromethanesulfonimide column.TABLE 1 Separation of compounds on (1S, 2R)-(+)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)imidate column* T # Compound Structure (° C.)k₁ α 1 Sec-Phenethyl alcohol

120 7.64 1.11 2 1-Phenyl-1-propanol

120 10.1 111 3 1-Phenyl-1-butanol

120 15.3 1.07 4 α-Cyclopropyl- benzyl alcohol

100 37.4 1.03 5 α-Phenyl ethyl amine (TFA derivative)

100 84.1 1.02 6 β-Pinene Oxide

100 12.3 1.03 7 o-Methylphenyl- methyl sulfoxide

140 73.3 1.03 8 o-Chlorophenyl- methyl sulfoxide

140 35.4 1.02 9 o-Bromophenyl- methyl sulfoxide

140 59.2 1.02 10 m-Methylphenyl- methyl sulfoxide

120 241 1.01 11 m-Chlorophenyl- methyl sulfoxide

120 196 1.01 12 m-Bromophenyl- methyl sulfoxide

120 374 1.01 13 trans-1,2- cyclohexandiol

120 21.4 1.10 14 trans-2-Phenyl-1- cyclohexanol

100 100 1.02*Column length: 8 meters, flow rate: 1 ml/mink₁ is the retention factor for the first enantiomerα is the ratio of retention times for the enantiomers

All of the compounds listed in Table 1 can form hydrogen bonds with thehydroxyl group on the first chiral center of the chiral ionic liquidstationary phase. A 13 meter (1S,2R)-(+)-N,N-dimethylephedriniumtrifluoromethanesulfonimide column was chosen to undergo a TFAderivatization process.²⁴ The new column was then tested against all thecompounds in Table 1. The experimental results showed that only thesulfoxides can be resolved enantiomerically. Nevertheless, theenantioselectivity became worse. It was also determined that thehydroxyl group on the first chiral center of the chiral stationary phasein this instance was important for the chiral recognition. While theforgoing separations were conducted using gas chromatography, OCILs maybe used in the same way in liquid chromatography, including highperformance liquid chromatography or HPLC.

EXAMPLE 1

A reaction gives about 3% enantiomeric excess (e.e.) when theN,N-dimethylephedrinium.NTf2 were used as a cosolvent. The reaction is areduction of methyl phenyl ketone by NaBH₄ run at room temperature. Thereaction mixture was analyzed by GC using a 20 m Chiraldex™ G-PN column.

REFERENCES

-   1. Fischer, T.; Sethi, A.; Welton, T.; Woolf, J. Tetrahedron Lett.    1999, 40, 793.-   2. Lee, C. W. Tetrahedron Lett. 1999, 40, 2461.-   3. Ludley, P.; Karodia, N. Tetrahedron Lett. 2001, 42, 2011.-   4. Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chemistry.    1999, 1, 23.-   5. Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon, K. R. Chem.    Commun. 1998, 2097.-   6. Stark, A.; Maclean, B. L.; Singer, R. D. J. Chem. Soc., Dalton    Trans. 1999, 63.-   7. Chauvin, Y. L.; Mussmann, L.; Olivier, H. Angew. Chem. Int. Ed.    Commun. 1996, 34, 2698.-   8. Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; Souza R. F. de;    Dupont, J. Polyhedron, 1996, 15, 1217.-   9. Aqueous-Phase Organometallic Catalysis: Concepts and    Applications; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:    Weinheim, 1998.-   10. Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.; Visser, A.    E.; Rogers, R. D. Chem. Commun. 1998, 1765.-   11. Branco, L. C.; Crespo, J. G.; Afonso, C. A. M. Angew. Chem. Int.    Ed. Commun. 2002, 41, 2771.-   12. Armstrong, D. W.; He, L.; Liu, Y.-S. Anal. Chem. 1999, 71, 3873.-   13. Anderson, J. L.; Armstrong, D. W. Anal. Chem. 2003, 75, 48-51.-   14. Barber, D. W.; Phillips, C. S. G.; Tusa, G. F.; Verdin, A. J.    Chem. Sco. 1959, 18.-   15. Pachole, F.; Butler, H. T.; Poole, C. F. Anal. Chem. 1982, 54,    1938.-   16. Poole, C. F.; Butler, H. T.; Coddens, M. E.; Dhanesar, S. C.;    Pacholec, F. J. Chromatogr. 1984, 289, 299.-   17. Furton, K. G.; Poole, C. F. Anal. Chem. 1987, 59, 1170.-   18. Pomaville, R. M.; Poole, C. F. Anal. Chem. 1988, 60, 1103.-   19. Poole, S. K.; Poole, C. F. Analyst 1995, 120, 289-294.-   20. Berthod, A.; He, L.; Armstrong, D. W. Chromatographia 2001, 53,    63.-   21. Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P. Tetrahedron    Lett. 1997, 38, 3097.-   22. Wasserscheid, P.; Bösmann, A.; Bolm, C. Chem. Commun. 2002, 200.-   23. Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591.-   24. Chiraldex handbook, 6^(th) edition, Advanced Separation    Technologies, 2002, 8.

1. A chiral cation containing optically enhanced ionic liquid in whichat least one enantiomer is enhanced by at least about 2%.
 2. The chiralcation containing optically enhanced ionic liquid of claim 1 in which atleast one enantiomer is enhanced by at least about 10%.
 3. The chiralcation containing optically enhanced ionic liquid of claim 1 in which atleast one enantiomer is enhanced by at least about 20%.
 4. The chiralcation containing optically enhanced ionic liquid of claim 1 in which atleast one enantiomer is substantially optically pure.
 5. The chiralcation containing optically enhanced ionic liquid of claim 1 comprisingonly at least one enantiomerically pure enantiomer.
 6. A chiral anioncontaining optically enhanced ionic liquid which is not a lactate. 7.The chiral anion containing optically enhanced ionic liquid of claim 6having a melting point of 100° C. or less.
 8. A chiral anion containingoptically enhanced ionic liquid in which at least one enantiomer isenhanced by at least about 2%.
 9. The chiral anion containing opticallyenhanced ionic liquid of claim 8 in which at least one enantiomer isenhanced by at least about 10%.
 10. The chiral anion containingoptically enhanced ionic liquid of claim 8 in which at least oneenantiomer is enhanced by at least about 20%.
 11. The chiral anioncontaining optically enhanced ionic liquid of claim 8 in which at leastone enantiomer is substantially optically pure.
 12. The chiral cationcontaining optically enhanced ionic liquid of claim 8 comprising only atleast one enantiomerically pure enantiomer.
 13. The asymmetric synthesisof a compound comprising the steps of: conducting a chemical reaction onat least one reactant in the presence of an OCIL to produce a reactionproduct, and recovering said reaction product; wherein said reactionproduct is optically active and either only one enantiomer will bepresent or one enantiomer will be present in an amount which is greaterthan the other enantiomer of said reaction product.
 14. An asymmetricmixture of enantiomers produced in accordance with the process of claim13.
 15. An enantiomerically pure enantiomer produced in accordance withthe process of claim
 13. 16. A method for deracemization of a racemiccompound comprising the steps of: conducting a chemical reaction on atleast one racemic reactant in the presence of an OCIL, and producing areaction product that is optically enhanced.
 17. An asymmetric mixtureof enantiomers produced in accordance with the process of claim
 16. 18.An enantiomerically pure enantiomer produced in accordance with theprocess of claim
 16. 19. A chemical reaction comprising the steps of:mixing, dissolving, dispersing or suspending at least one first reactantin a substantially pure OCIL or in a solvent including a substantiallypure OCIL and reacting said at least one first reactant with at leastone second reactant, at least one catalyst or said OCIL so as to producea reaction product which is changed in structure or properties whencompared to said at least one first reactant.
 20. The chemical reactionof claim 19 wherein said OCIL contains a chiral cation.
 21. The chemicalreaction of claim 19 wherein said OCIL contains a chiral anion.
 22. Thereaction product produced in accordance with the process of claim 19.23. The reaction product produced in accordance with the process ofclaim
 20. 24. The reaction product produced in accordance with theprocess of claim
 21. 25. The reaction product produced in accordancewith the process of claim 19 wherein said reaction product isasymmetric.
 26. A column for use in chromatography comprising: a columnand a stationary phase which is an OCIL associated therewith.
 27. Thecolumn of claim 26 wherein said column is a capillary and saidstationary phase is coated on an inner surface of said capillary. 28.The column of claim 26 wherein said stationary phase is absorbed,adsorbed or coated on a solid support which is packed into said column.29. A method of separating optical isomers comprising the steps of:mixing, dissolving, dispersing or suspending optical isomers in a mobilephase, introducing said optical isomers into a column that includes atleast one OCIL as a stationary phase, and advancing said mobile phaseand said optical isomers through said column so as to resolve at leastone of said optical isomers.
 30. An OCIL having the following structure:


31. An optically enhanced chiral ionic liquid composed of at least onesalt comprising both chiral anions and chiral cations.